Quality of life, prognostic and predictive factors in vulnerable older patients with metastatic colorectal cancer receiving palliative chemotherapy: The randomized NORDIC9-study

Gabor Liposits*

*Corresponding author for this work

Research output: ThesisPh.D. thesis

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Abstract

Colorectal cancer is accountable for the second highest mortality among all cancer types and predominantly affects adults aged 70 years or older. Owing to the aging populations worldwide, the number of older adults with cancer is steeply increasing including those with colorectal cancer.
Despite the majority of patients with metastatic colorectal cancer (mCRC) is older than 70 years, the optimal treatment strategy is less clear due to the underrepresentation of older adults in randomized controlled trials and very few clinical trials dedicated to this large group of patients. The investigator-initiated randomized phase II study, the NORDIC9, prospectively tested an approach among older patients with mCRC who were not considered being candidates for full-dose combination treatment; reduced-dose combination vs full-dose single agent chemotherapy. The NORDIC9-study included 160 patients from four Nordic countries between March 2015 and October 2017 and established that reduced-dose combination chemotherapy resulted in significant prolonged progression-free survival with a trend towards prolonged overall survival, fewer toxicities, and hospital admissions compared to full-dose monotherapy. These encouraging results added important knowledge to the literature and raised several questions regarding the patients' quality of life and the potential prognostic and predictive factors in the NORDIC9 cohort. Therefore, we conducted four sub-studies further investigating quality of life, the prognostic value of systemic inflammation explored through plasma biomarkers, the prognostic value of physical functioning, and the RAS/BRAF mutation status. Finally, we also explored the predictive value of treatment allocation according to RAS/BRAF status.
We found that patients receiving reduced-dose combination treatment maintained their quality of life and physical performance and had lower symptom burden compared to the full-dose monotherapy arm. The results of the biomarker analysis clearly demonstrated that patients who had elevated plasma C-reactive protein (CRP) at inclusion had significant shorter overall survival and progression-free survival than those with normal level of CRP, regardless of treatment.
When analyzing survival outcomes according to physical performance, we found that Eastern Cooperative Oncology Group performance status and Vulnerable Elderly Survey-13 were proper tools to foresee shorter survival. These tools evaluate activities of daily living and instrumental activities of daily living in different ways, although, patients with higher scores on these scales had significantly higher risk for shorter survival.
RAS/BRAF mutation status is a cornerstone of the therapeutic decision-making in young and fit adults with mCRC; however, its real clinical impact on daily clinical practice is less known and its potential role determining the use of targeted therapies is less established in older adults with mCRC.
Our results demonstrate that patients whose mCRC was driven by BRAFV600E mutation had significantly shorter overall survival and progression-free survival compared to patients presented with other molecular sub-types. In this particular group of patients with BRAFV600E mutation, the use of reduced-dose combination chemotherapy resulted in a remarkable overall survival advantage compared to the full-dose monotherapy arm.
I conclude that reduced-dose combination chemotherapy is the treatment of choice in older adults with mCRC who are ineligible for intensive chemotherapy. Its use resulted in prolonged survival, less toxicities, fewer hospital admissions, and preserved quality of life and physical performance. Using biomarkers, measurements of physical functioning, and RAS/BRAF mutation status provide important prognostic information and have therapeutic implication, thus, contribute to proper patient selection. These factors may influence survival and enhance communication in the shared decision-making process. 
Original languageEnglish
Awarding Institution
  • University of Southern Denmark
Supervisors/Advisors
  • Pfeiffer, Per, Principal supervisor
  • Ryg, Jesper, Co-supervisor
  • Winther, Stine Brændegaard, Co-supervisor
  • Skuladottir, Halla, Co-supervisor, External person
Date of defence12. Apr 2024
Publisher
DOIs
Publication statusPublished - 13. Mar 2024

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  • Nordic9-study

    Liposits, G. I. (PhD student), Pfeiffer, P. (Supervisor), Winther, S. B. (Co-supervisor), Ryg, J. (Co-supervisor) & Skuladottir, H. (Co-supervisor)

    01/09/202031/12/2023

    Project: PhD Project

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